Feline immunodeficiency virus (FIV) is a lentivirus that causes an AIDS-like syndrome in the domestic cat. A clade C FIV, termed FIV-Cpg, is particularly pathogenic and causes a rapid and precipitous decline in CD4+ T cells, thymus atrophy, severe neutropenia, and death due to opportunistic infections in approximately 60% of infected animals within the five months of infection. The purpose of these studies is to molecularly clone and characterize this isolate of FIV-C and to use this molecular clone to map pathogenic determinants of the virus. In the initial three years of the proposal, we have succeeded in cloning and obtaining the complete nucleotide sequence of an infectious clone termed FIV-C36 that, in preliminary in vivo analyses was shown to cause disease course similar to the uncloned FIV-Cpg. In addition, we have cloned and characterized an additional 22 envelope sequences from the thymuses of cats that have died as a result of FIV-Cpg infection. We have also prepared an immunoadhesin in which the surface glycoprotein of SU is fused to the Fc domain of a human antibody and have initiated studies to define receptor interactions of FIV-C36. In the continuation studies, we propose to 1) perform detailed in vivo analyses to assess the pathogenic potential of FIV-C36, including assessment of tissue distribution and magnitude and kinetics of virus burden; 2) prepare chimeric FIVs between FIV-C36 and FIV-A-PPR in order to map determinants of pathogenesis; and 3) to assess the function of the envelope gene of FIV-C by analyzing the receptor binding properties of wild type and chimeric FIV-C Envelope proteins, expressed as immunoadhesins. These studies will allow the mapping of determinants of pathogenesis for FIV-C and provide the molecular background for detailed ex vivo and in vivo studies and for development of intervention strategies in an accelerated model.